Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan;38(1):24-6. Epub 2005 Dec 20 PubMed.

Comments

- Dennis Selkoe
  Co-Director, Brigham and Women's Hospital's Ann Romney Center for Neurologic Diseases
- Posted: 20 Dec 2005
- News: APP Double Dose Causes Early Onset AD
This is a very exciting development that strongly supports the amyloid hypothesis of AD causation. It appears to be symmetrical with the discovery of α-synuclein duplication (and triplication) in otherwise phenotypically normal individuals in the causation of PD. It suggests that increased expression of wild-type APP—whether from enhanced gene dosage, as in these families, or perhaps from alterations in regulatory elements of the APP gene in other families yet to be discovered—can directly cause AD.

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- Elizabeth M. Fisher
  Institute of Neurology
- Posted: 20 Dec 2005
- News: APP Double Dose Causes Early Onset AD
This is a very nice piece of work. First, it highlights the important issue of gene duplication in neurodegenerative disease.
Second, the paper is very important for answering the question "Is duplication of APP alone (as in Down syndrome) sufficient to cause AD?" The authors have narrowed the AD region down to just four genes. This almost answers this question, but the genome may still have suprises up its sleeve, so it would be great for other labs to carry out similar analyses and see what the minimal duplicated region is to cause AD.

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- Alison Goate
  Icahn School of Medicine at Mount Sinai
- Posted: 20 Dec 2005
- News: APP Double Dose Causes Early Onset AD
This is a very interesting paper that is totally consistent with the Aβ hypothesis. The observation that duplication of APP causes early onset AD and CAA is consistent with the observations in Down syndrome (DS) and confirms that AD pathology in DS is due to APP overexpression. The presence of CAA is also interesting and supports data from the transgenic mice, DS, and other FAD mutations that overproduction of Aβ40 leads to CAA, while increased Aβ42 is associated with parenchymal plaques. This also fits with the observations in PD, where duplication and triplication of α-synuclein have been associated with early onset PD.

I am surprised by the frequency of the duplications in their early onset FAD samples (8 percent of FAD cases) and by the fact that each of the duplications is different but not associated with any other phenotype despite the presence of other genes in the duplicated region.

Lastly, these studies really beg the question: Does variation in APP expression contribute to risk for late-onset AD? We posed this possibility in the first mutation papers back in 1991/1992 but I don't think the question has been adequately addressed yet. This new data makes it all the more important to tackle this question.

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- Barbara Tate
  Satori Pharmaceuticals
- Posted: 22 Dec 2005
- News: APP Double Dose Causes Early Onset AD
This brief paper describes a rare genetic abnormality in five different families with autosomal dominant, early onset Alzheimer disease with cerebral amyloid angiopathy. Using three different techniques, this research group was able to establish that a very small portion of chromosome 21 is duplicated in these families. The chromosomal region includes the locus for APP, as well as other genes. Because the duplicated region is slightly different among the five families but in all families the APP locus is included, the conclusion that overproduction of APP is responsible for the disease is compelling. The disease phenotype is similar in all five families. It consists of progressive AD with abundant dense-core and diffuse amyloid deposits as well as neurofibrillary tangles, giving support to the hypothesis that overproduction of the amyloid protein initiates a cascade of events that leads to both plaques and tangles.

In addition, the patients studied by Rovelet-Lecrux et al. have severe cerebral amyloid angiopathy (CAA), and this vascular amyloid deposition is primarily composed of Aβ40. Mutations in Aβ have been discovered in several autosomal dominant cerebral amyloid angiopathies, leading to the hypothesis that amino acid substitutions within the Aβ sequence generate a peptide that has a propensity to aggregate in the microvasculature. However, CAA is also found in sporadic AD, as well as Down syndrome, and is now reported in these families with duplication of the APP locus. Thus, overproduction alone of wild-type Aβ can precipitate development of CAA.

In the patients reported here, the parenchymal amyloid deposits are primarily composed of Aβ42, surrounded by Aβ40. A tendency of Aβ40 to aggregate in the vasculature versus primarily parenchymal deposition of Aβ42 suggests that these peptides are either produced or processed differently within different cell types. Distinct pathological structures characterize the brains of AD patients with mutations of the presenilins (PS1 and 2), where overproduction of Aβ42 is a consistent finding. The comparison of the nature of lesions within each of these genetic variations of AD may help us understand molecular events that are upstream of amyloid deposition.

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- Joy Snider
  Washington University School of Medicine
- Posted: 22 Dec 2005
- News: APP Double Dose Causes Early Onset AD
This study by Rovelet-Lecrux et al. is interesting in several aspects: It points out that gene duplication may be a more common cause of early onset familial Alzheimer disease than previously suspected, and it highlights the coexistence of two forms of amyloid pathology, parenchymal and vascular.

The authors did not comment on whether immunohistochemical stains for synuclein or ubiquitin were performed. It will be interesting to study the interactions between the pathological burden of amyloid (both parenchymal and vascular) and Lewy body pathology. Specifically, it will be interesting to determine whether the coexistence of Lewy body pathology with Alzheimer-type pathology in early onset AD is limited to people harboring presenilin 1 mutations, or whether it is a more general feature seen in some patients independent of the gene mutation (or duplication).

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- Deborah Uetz
- Posted: 30 Dec 2005
- News: APP Double Dose Causes Early Onset AD
This is a very interesting paper. As the daughter of an Alzheimer's patient it is very important to know that progress is being made. Well done.

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- Andre Delacourte
  Inserm
- Posted: 02 Jan 2006
A great discovery. I agree with John Hardy that this discovery shows, once and for all, the major role of APP dysfunction n Alzheimer disease.

At first sight, the paper strongly reinforces the amyloid cascade hypothesis. However, in these familial cases, like in all other familial and sporadic AD cases, dementia occurs with a neocortical tauopathy, showing also that AD explanation is more likely an APP-tau deleterious interaction.

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- Daniel Geschwind
- Posted: 02 Jan 2006
The role of copy number polymorphisms in human genetic variation has only recently been appreciated and only investigated in a few diseases. This provides the first evidence that gene copy number abberations, in addition to being a mechanism of Parkinson disease, can be a cause of AD. So, the discovery about a decade ago of the CMT duplication may have been just the tip of the iceberg.

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